{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:18:29Z","timestamp":1790817509641,"version":"4.1.0"},"reference-count":29,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background:<\/jats:title>\n                  <jats:p>Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods:<\/jats:title>\n                  <jats:p>BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA \u22650.5 years compared with calendar age.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion:<\/jats:title>\n                  <jats:p>This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2016-2941","type":"journal-article","created":{"date-parts":[[2016,10,6]],"date-time":"2016-10-06T18:23:05Z","timestamp":1475778185000},"page":"1458-1467","source":"Crossref","is-referenced-by-count":67,"title":["ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment"],"prefix":"10.1210","volume":"102","author":[{"given":"Manouk","family":"van der Steen","sequence":"first","affiliation":[{"name":"Dutch Growth Research Foundation, 3001 KB Rotterdam, The Netherlands;"},{"name":"Erasmus University Medical Center-Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolph","family":"Pfundt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Division of Genome Diagnostics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan J.W.H.","family":"Maas","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Division of Genome Diagnostics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willie M.","family":"Bakker-van Waarde","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roelof J.","family":"Odink","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita C.S.","family":"Hokken-Koelega","sequence":"additional","affiliation":[{"name":"Dutch Growth Research Foundation, 3001 KB Rotterdam, The Netherlands;"},{"name":"Erasmus University Medical Center-Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2016,10,6]]},"reference":[{"issue":"6","key":"2020071619411016000_B1","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1542\/peds.111.6.1253","article-title":"International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001","volume":"111","author":"Lee","year":"2003","journal-title":"Pediatrics"},{"issue":"3","key":"2020071619411016000_B2","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1210\/jc.2006-2017","article-title":"Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society","volume":"92","author":"Clayton","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2020071619411016000_B3","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1203\/00006450-199508000-00022","article-title":"Children born small for gestational age: do they catch up?","volume":"38","author":"Hokken-Koelega","year":"1995","journal-title":"Pediatr Res"},{"key":"2020071619411016000_B4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000053080","article-title":"Children born small-for-gestational age: postnatal growth and hormonal status","volume":"49","author":"Albertsson-Wikland","year":"1998","journal-title":"Horm Res"},{"issue":"9","key":"2020071619411016000_B5","first-page":"3064","article-title":"Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial","volume":"84","author":"Sas","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2020071619411016000_B6","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1210\/jc.2002-021172","article-title":"Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial","volume":"88","author":"Van Pareren","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2020071619411016000_B7","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1203\/01.PDR.0000148716.71231.81","article-title":"Final height in short children born small for gestational age treated with growth hormone","volume":"57","author":"Dahlgren","year":"2005","journal-title":"Pediatr Res"},{"issue":"4","key":"2020071619411016000_B8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrg2322","article-title":"Heritability in the genomics era\u2013concepts and misconceptions","volume":"9","author":"Visscher","year":"2008","journal-title":"Nat Rev Genet"},{"issue":"3","key":"2020071619411016000_B9","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.beem.2008.02.001","article-title":"Single gene mutations causing SGA","volume":"22","author":"Walenkamp","year":"2008","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"issue":"12","key":"2020071619411016000_B10","doi-asserted-by":"crossref","first-page":"4717","DOI":"10.1210\/jc.2008-1502","article-title":"Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype","volume":"94","author":"Ester","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"2020071619411016000_B11","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1136\/jmg.2009.070730","article-title":"Phenotype-genotype correlation in a familial IGF1R microdeletion case","volume":"47","author":"Veenma","year":"2010","journal-title":"J Med Genet"},{"issue":"8","key":"2020071619411016000_B12","doi-asserted-by":"crossref","first-page":"E1510","DOI":"10.1210\/jc.2014-1332","article-title":"Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations","volume":"99","author":"Nilsson","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"7-8","key":"2020071619411016000_B13","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1515\/jpem-2014-0450","article-title":"Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene","volume":"28","author":"Quintos","year":"2015","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"1","key":"2020071619411016000_B14","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ajhg.2008.12.001","article-title":"A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan","volume":"84","author":"Tompson","year":"2009","journal-title":"Am J Hum Genet"},{"issue":"4","key":"2020071619411016000_B15","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1210\/jc.2005-1663","article-title":"High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age","volume":"91","author":"van Dijk","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"2020071619411016000_B16","doi-asserted-by":"crossref","first-page":"4096","DOI":"10.1210\/jc.2012-1987","article-title":"Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial","volume":"97","author":"Lem","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2020071619411016000_B17","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S0022-3476(69)80224-6","article-title":"Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation","volume":"74","author":"Usher","year":"1969","journal-title":"J Pediatr"},{"issue":"3","key":"2020071619411016000_B18","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1203\/00006450-200003000-00006","article-title":"Continuing positive secular growth change in The Netherlands 1955-1997","volume":"47","author":"Fredriks","year":"2000","journal-title":"Pediatr Res"},{"key":"2020071619411016000_B19","volume-title":"Radiographic Atlas of Skeletal Development of the Hand and Wrist","author":"Greulich","year":"1959","edition":"2nd ed."},{"issue":"2","key":"2020071619411016000_B20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ajhg.2009.12.018","article-title":"A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans","volume":"86","author":"Stattin","year":"2010","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2020071619411016000_B21","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1373\/clinchem.2014.225250","article-title":"Translating sanger-based routine DNA diagnostics into generic massive parallel ion semiconductor sequencing","volume":"61","author":"Diekstra","year":"2015","journal-title":"Clin Chem"},{"issue":"1","key":"2020071619411016000_B22","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13023-016-0459-2","article-title":"The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases","volume":"11","author":"Gibson","year":"2016","journal-title":"Orphanet J Rare Dis"},{"issue":"2","key":"2020071619411016000_B23","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/ajmg.1320370223","article-title":"Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen","volume":"37","author":"Anderson","year":"1990","journal-title":"Am J Med Genet"},{"issue":"3","key":"2020071619411016000_B24","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1086\/444401","article-title":"A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis","volume":"77","author":"Gleghorn","year":"2005","journal-title":"Am J Hum Genet"},{"issue":"8","key":"2020071619411016000_B25","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.joca.2007.11.009","article-title":"Familial osteochondritis dissecans associated with early osteoarthritis and disproportionate short stature","volume":"16","author":"Stattin","year":"2008","journal-title":"Osteoarthr Cartil"},{"issue":"3","key":"2020071619411016000_B26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1046\/j.1365-2613.1997.210355.x","article-title":"Intrinsic control of vascularization in developing cartilage rudiments","volume":"78","author":"Fenwick","year":"1997","journal-title":"Int J Exp Pathol"},{"issue":"2","key":"2020071619411016000_B27","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ydbio.2009.02.024","article-title":"Aggrecan modulation of growth plate morphogenesis","volume":"329","author":"Domowicz","year":"2009","journal-title":"Dev Biol"},{"issue":"2","key":"2020071619411016000_B28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000324105","article-title":"Short stature due to SHOX deficiency: genotype, phenotype, and therapy","volume":"75","author":"Binder","year":"2011","journal-title":"Horm Res Paediatr"},{"issue":"3","key":"2020071619411016000_B29","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1365-2265.2007.02901.x","article-title":"An evaluation of the relationship between adult height and health-related quality of life in the general UK population","volume":"67","author":"Christensen","year":"2007","journal-title":"Clin Endocrinol (Oxf)"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/102\/5\/1458\/16629896\/jc.2016-2941.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/102\/5\/1458\/16629896\/jc.2016-2941.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T04:44:51Z","timestamp":1594961091000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/102\/5\/1458\/3797280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,6]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2016-2941","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,5,1]]},"published":{"date-parts":[[2016,10,6]]}}}